Effects of PI(4,5)P₂ concentration on the F‐BAR domain membrane binding as revealed by coarse‐grained simulations

Abstract

Bin/Amphyphysin/Rvs (BAR) domain proteins form a key link between membrane remodeling and cytoskeleton dynamics. They are dimers that bind to membranes via electrostatic interactions with different preferences toward negatively charged lipids. In the present article, we examine the interactions of the F‐BAR domain of nervous wreck (Nwk) with phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P2)‐containing membranes using coarse‐grained molecular dynamics. We demonstrated PI(4,5)P2 concentration effects, identified the sequence of events that underlies the protein binding and identified amino acids involved in protein–lipid interactions. Our simulations point out the primary role of the basic stretch at the tips of the dimer, which anchors the protein to the membrane and initiates the binding process. When the PI(4,5)P2 concentration is high, the protein stably associates with the membrane by its concave surface or by the opposite side. At low PI(4,5)P2 concentration, the former orientation becomes more favorable; also a state with only one tip bound is observed, due to the weaker attachment and more pronounced association/dissociation events. Our results provide a theoretical model that describes the lipid‐binding behavior of Nwk observed in vitro.

Receptor‐Free Signaling at Curved Cellular Membranes

“…[109] MD studies further demonstrated the importance of positive residues on the BAR domains and lipid composition as parameters in curvature-dependent protein recruitment. [110,111] As such, MD has positioned itself as a significant contributor in determining the role of curvature during mechanical deformation associated with cellular processes and signaling. Yet, atomistic and coarsegrain MD studies rely on force fields that represent the basic physical properties of proteins and lipids as the membrane bends.…”